Theophylline derivatives

ABSTRACT

Derivatives of theophylline substituted at the 7 position with various substituents containing a homopiperazine nucleus. The compounds can be prepared reacting theophylline or reactive intermediate containing same with a homopiperazine compound. The compounds exhibit antihistaminic activity and vasodilating activity.

This is a division of application Ser. No. 307 458 filed Oct. 1, 1981,which is a continuation of application Ser. No. 171 052, filed July 22,1980 both abandoned.

This invention relates to theophylline derivatives which exhibitexcellent pharmaceutical activity and processes for the preparation ofthe same. More particularly, this invention relates to theophyllinederivatives having the general formula: ##STR1## in which X represents agroup having the formula --(CH₂)_(n) --, in which n is an integer of1-6, or a group having the formula ##STR2## and R represents

a lower alkyl group;

a group having the formula ##STR3## in which A stands for a group havingthe formula --(CH₂)_(m) --, in which m is an integer of 0-2, a grouphaving the formula ##STR4## a group having the formula ##STR5## or agroup having the formula --CO--CH═CH--, and Y₁, Y₂ and Y₃ are the sameor different and each stands for the hydrogen atom, a lower alkyl group,a lower alkoxy group, a lower alkylsulfonyl group, a halogen atom or thenitro group;

a group having the formula --Z--OH, in which Z stands for a group havingthe formula --(CH₂)_(a) --, in which a is an integer of 1-3, or a grouphaving the formula ##STR6##

a group having the formula --COR₁, in which R₁ stands for the hydrogenatom or a lower alkyl group; or

a group having the formula ##STR7## and acid addition salts thereof, andfurther relates to processes for the preparation of the same.

In the aforementioned general formula [I], the terms "lower alkylgroup", "lower alkoxy group" and "lower alkylsulfonyl group" set forthin the definitions for Y₁, Y₂, Y₃ and R₁ are straight or branched chainalkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl,isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl,1-ethylpropyl, isoamyl or n-hexyl, and corresponding C₁ to C₆ alkoxygroup and alkylsulfonyl groups.

The term "halogen atom" specifically means chlorine, bromine, iodine orfluorine.

The compounds of the present invention having the formula [I] can easilybe reacted with a pharmaceutically acceptable inorganic or organic acidto obtain an acid addition salt. Examples of the inorganic acids includehydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid,and examples of the organic acids include maleic acid, fumaric acid,succinic acid, acetic acid, malonic acid, citric acid and benzoic acid.

Typical examples of the compounds of the present invention include:

7-{[4-phenylhomopiperazino-(1)]methyl}-theophylline;

7-{[4-methylhomopiperazino-(1)]methyl}-theophylline;

7-{[4-p-chlorobenzylhomopiperazino-(1)]methyl}-theophylline;

7-{[4-formylhomopiperazino-(1)]ethyl}-theophylline;

7-{[4-methylhomopiperazino-(1)]ethyl}-theophylline;

7-{[4-phenylhomopiperazino-(1)]ethyl}-theophylline;

7-{[4-p-chlorobenzylhomopiperazino-(1)]ethyl}-theophylline;

7-{[4-(3,4-dichlorobenzyl)homopiperazino-(1)]ethyl}-theophylline;

7-{[4-methylhomopiperazino-(1)]propyl}-theophylline;

7-{[4-(2-hydroxyethyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-(3-hydroxypropyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-(2-hydroxypropyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-propylcarbonyl-homopiperazino(1)]propyl}-theophylline;

7-{[4-(2-pyridyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-phenylhomopiperazino-(1)]propyl}-theophylline;

7-{[4-benzylhomopiperazino-(1)]propyl}-theophylline;

7-{[4-p-chlorobenzylhomopiperazino-(1)]propyl}-theophylline;

7-{[4-(2-chlorobenzyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-(2,4-dichlorobenzyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-(3,4-dichlorobenzyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-p-fluorobenzylhomopiperazino-(1)]propyl}-theophylline;

7-{[4-p-nitrobenzylhomopiperazino-(1)]propyl}-theophylline;

7-{[4-p-methoxybenzylhomopiperazino-(1)]propyl}-theophylline;

7-{[4-(3,4-dimethoxybenzyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-(2,3,4-trimethoxybenzyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-(2,6-dimethoxybenzyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-(pyrimidinyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-(3,4-dichlorobenzoyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-p-methylsulfonylbenzoylhomopiperazino-(1)]propyl}-theophylline;

7-{[4-(methylphenylmethyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-phenethylhomopiperazino-(1)]propyl}-theophylline;

7-{[4-(phenylvinylcarbonyl)homopiperazino-(1)]propyl}-theophylline;

7-{[4-p-chlorobenzylhomopiperazino-(1)]butyl}-theophylline;

7-{[4-p-fluorobenzylhomopiperazino-(1)]butyl}-theophylline; and

7-{[4-p-nitrobenzylhomopiperazino-(1)]butyl}-theophylline.

The theophylline derivatives provided by the present invention are allbelieved to be novel compounds that have not heretofore been disclosed.They have low toxicity and a long lasting, remarkable, antihistaminicaction. The compounds of the present invention are further effective inthe treatment of a variety of allergic respiratory diseases such asallergic rhinitis and bronchial asthema and a variety of allergic skindiseases such as urticaria, eczema, dermatitis and pruritus cutaneous.Furthermore, the compounds of the present invention have a remarkablevasodilating action. In other words, the compounds improve not only theperipheral blood flow, but also remarkably improve the blood flow in thebrain and the coronary artery. Accordingly, the compounds of the presentinvention are effective as medicines for treating a variety of diseasesarising from the perfusion of peripheral blood flow and for improvingthe insufficiency of cerebral blood vessels and their sequela, and alsofor treating angina pectoris, myocardial infarction and so forth.

The compounds of the present invention having the formula [I] can beprepared by a variety of processes. Among them, one of the generallyapplicable processes for the preparation is illustrated as follows.

(1) Process A ##STR8##

In the formulae shown in the above-illustrated scheme, Hal means ahalogen atom and X and R both have the same meanings as definedhereinbefore.

As shown in the above scheme, a compound having the general formula (II)and a compound having the general formula (III) are caused to react togive the desired compound having the general formula (I).

The present reaction can be carried out in the absence of a solvent.Alternatively, the reaction can be carried out in the presence of asolvent that does not participate in the reaction, such as a loweralcohol, e.g., methanol, ethanol, propanol or isopropanol, a benzenegroup solvent, e.g., benzene, toluene or xylene, or an ether groupsolvent, e.g., ethyl ether or tetrahydrofuran.

The present reaction can proceed even at room temperature, but thereaction preferably is carried out at the refluxing temperature of thesolvent employed. The reaction proceeds more smoothly in the presence ofdeacidizing agent such as triethylamine, an alkali hydrogen carbonate,an alkali carbonate or pyridine.

(2) Process B

The desired compound having the general formula (I) in which X is abridging group represented by --(CH₂)_(n) -- and n is 1 can be preparedby another process illustrated below. ##STR9##

In the formulae shown in the above-illustrated scheme, R has the samemeaning as defined hereinbefore.

More in detail, a compound having the general formula (IV), a compoundhaving the general formula (III) and formaldehyde are caused to react ina lower alcohol solvent such as methanol, propanol or isopropanol. Thereaction is carried out under reflux of the solvent employed.

(3) Process C ##STR10##

In the formulae shown in the above-illustrated scheme, Hal means ahalogen atom, and X and R have the same meanings as definedhereinbefore.

Thus, a compound having the general formula (VI) and a compound havingthe general formula (VII) are caused to react to give the desiredcompound having the general formula (I).

For instance, a compound having the general formula (I) in which Rrepresents a group having the formula ##STR11## in which Y₁, Y₂ and Y₃have the same meanings as defined hereinbefore, can be preparedfollowing the exemplary scheme illustrated below. ##STR12##

For another instance, a compound having the general formula (I) in whichR represents a group having the formula --(CH₂)_(a) --OH, in which a hasthe same meaning as defined hereinbefore, can be prepared following theexemplary scheme illustrated below. ##STR13##

The present reaction can be carried out in the absence of a solvent.Alternatively, the reaction can be carried out in the presence of asolvent that does not participate in the reaction, such as a loweralcohol, e.g., methanol, ethanol, propanol or isopropanol, a benzenegroup solvent, e.g., benzene, toluene or xylene, or an ether groupsolvent, e.g., ethyl ether or tetrahydrofuran.

The present reaction can proceed even at room temperature, but thereaction preferably is carried out at the refluxing temperature of thesolvent employed. The reaction proceeds more smoothly in the presence ofan appropriate deacidizing agent such as triethylamine, an alkalihydrogen carbonate, an alkali carbonate or pyridine.

The remarkable pharmacological activities of the compounds of thepresent invention are illustrated below for representative compounds ofthe present invention.

1. Antihistaminic action

The terminal ileum was removed from a starved guinea-pig and set up inan organ bath containing Tyrode solution maintained at 26° C.Contractile tension was recorded isometrically under a tension of 1.5 gwith a strain-gauge transducer. After obtaining control response tohistamine (10⁻⁶ M), antagonists were added to the bath and allowed toremain in contact with the tissue for 3 minutes. Contractile response tohistamine in the presence of the antagonists was recorded and theinhibitory rate was calculated according to the following equation:##EQU1## The tissue was then washed at 10 min intervals with freshTyrode solution. Contractile response to histamine was tested after eachwash in order to study the duration of action of the antagonists.

The results are shown in Table 1, in which compounds designated bynumerals are as follows.

Control compounds

(1): Promethazine

(2): Cinnarizine

(3): Homochlorcyclizine ##STR14##

                                      TABLE 1                                     __________________________________________________________________________              Concen-                                                                            Inhibitory rate (%)                                                      tration                                                                            Before                                                                             After washing                                             Test Sample                                                                             (M)  washing                                                                            1st                                                                              2nd                                                                              3rd                                                                              4th                                                                              5th                                                                              6th                                                                              7th                                     __________________________________________________________________________    Control Compound                                                              (1)       10.sup.-7                                                                          87   77 56 37                                                            10.sup.-8                                                                          37   44                                                        (2)       10.sup.-6                                                                          74   81 71 65                                                            10.sup.-7                                                                           2   52 37 26 19                                               (3)       10.sup.-7                                                                          88   84 63 55 39 25 33                                                   10.sup.-8                                                                          13   46 42                                                     Compound of the                                                               Invention                                                                     (4)       10.sup.-6                                                                          100  10  0                                                               10.sup.-7                                                                          64    4  0                                                               10.sup.-8                                                                          12    0                                                        (5)       10.sup.-6                                                                          100  84 65 58                                                            10.sup.-7                                                                          100  64 31 20  7  0                                                      10.sup.-8                                                                           2    7  4                                                     (6)       10.sup.-6                                                                          100  100                                                                 10.sup.-7                                                                          80   73 58 47 38 29 29 20                                                10.sup.-8                                                                          14   14 14  6                                                  (7)       10.sup.-6                                                                          96   100                                                                              100                                                                              100                                                                              83 87 85                                                   10.sup.-7                                                                          78   59 52 30                                                            10.sup.-8                                                                           6   42 46 46 42 32 18 14                                      (8)       10.sup.-7                                                                          65   55 28 28 20                                                         10.sup.-8                                                                          11   29 19                                                     (9)       10.sup.-6                                                                          100  27  5  0                                                            10.sup.-7                                                                          77   20 13  5  0                                                         10.sup.-8                                                                          10    7  7  1                                                  (10)      10.sup.-6                                                                          100  46 19                                                               10.sup.-7                                                                          65   16                                                                  10.sup.-8                                                                          21   12  0                                                     (11)      10.sup.-7                                                                          78   10  4  0                                                            10.sup.-8                                                                           0    0                                                        __________________________________________________________________________

The results shown in Table 1 clearly indicate that the compounds of thepresent invention exhibited a potent antihistaminic activity withcharacteristically long duration of action. Both the antihistaminicactivity and the duration of action of the compounds of the presentinvention were equal to or superior to those of the control compounds,i.e., promethazine, cinnarizine and homochlorcyclizine. Accordingly, thecompounds of the present invention are considered to be of excellentvalue as antihistamine drugs.

The present invention will be further described by reference to thefollowing illustrative examples, but these examples by no means restrictthe present invention.

EXAMPLE 1 7-{[4-Phenylhomopiperazino-(1)]methyl}theophylline

A mixture of 1.8 g of theophylline, 1.8 g of phenylhomopiperazine and1.2 g of 37% formaldehyde in ethanol was refluxed under stirring for 5minutes. The crystals deposited upon completion of the reaction werecollected by filtration.

Thus, the desired 7-{[4-phenylhomopiperazino-(1)]methyl}-theophyllinewas obtained. Yield 2.2 g and m.p. 106°-107° C.

Analysis for C₁₉ H₂₄ O₂ N₆ : Calculated (%): C, 61.93; H, 6.58; N,22.81. Found (%): C, 61.42; H, 6.51; N, 22.60.

EXAMPLE 2 7-{[4-p-Chlorobenzylhomopiperazino-(1)]ethyl}-theophylline

A mixture of 4.3 g of 7-(2-bromoethyl)theophylline, 3.4 g ofp-chlorobenzylhomopiperazine and 3.0 g of triethylamine in benzene wasrefluxed under stirring for 5 hours. The produced triethylaminehydrochloride was removed by filtration, and the filtrate was extractedwith dilute hydrochloric acid. The dilute hydrochloric acid phase wasseparated, made alkaline with dilute aqueous sodium hydroxide, andextracted with benzene. The solvent was then evaporated, and theresidual crude crystals were recrystallized from isopropyl alcohol.Thus, the desired7-{[4-p-chlorobenzylhomopiperazino-(1)]ethyl}-theophylline was obtained.Yield 3.2 g and m.p. 114°-115° C.

Analysis for C₂₁ H₂₇ O₂ N₆ Cl: Calculated (%): C, 58.52; H, 6.33; N,19.78. Found (%): C, 58.56; H, 6.33; N, 19.78.

EXAMPLE 37-{[4-β-Hydroxyethylhomopiperazino-(1)]propyl}-theophylline.dihydrochloride

(1) 7-[3-Homopiperazino-(1)]propyl-theophylline

A mixture of 35 g of 7-(3-bromopropyl)theophylline, 15 g ofN-formylhomopiperazine and 16 g of anhydrous potassium carbonate inethanol was refluxed under stirring for 10 hours. The depositedpotassium carbonate was removed by filtration and the filtrate was thenconcentrated under reduced pressure. The residue was hydrolyzed withdilute hydrochloric acid to give 33 g of the desired7-[3-homopiperazino-(1)]propyl-theophylline.

(2)7-{[4-β-Hydroxyethylhomopiperazino-(1)]propyl}-theophylline.dihydrochloride

A mixture of 3.2 g of the 7-[3-homopiperazino-(1)]propyl-theophyllineobtained in the above step (1), 1.6 g of ethylenechlorohydrin and 1.4 gof anhydrous potassium carbonate in ethanol was refluxed under stirringfor 19 hours. The potassium carbonate was then removed by filtration,and the filtrate was concentrated. To the residue was added dilutehydrochloric acid, and this was washed with chloroform and then madealkaline with dilute aqueous sodium hydroxide. An oil was separated fromthe aqueous solution, and this oil was extracted with chloroform. Thechloroform extract was evaporated to remove the solvent, and then theresidue was converted to its hydrochloride in a conventional manner. Thehydrochloride thus obtained was recrystallized from methanol to give 1.8g of the desired7-{[4-β-hydroxyethylhomopiperazino-(1)]propyl}-theophylline.hydrochloride.M.p. 183°-186° C. (decomposed).

Analysis for C₁₇ H₂₈ O₃ N₆.2HCl.1/2H₂ O: Calculated (%): C, 45.73; H,7.01; N, 18.83. Found (%): C, 45.20; H, 7.18; N, 18.59.

EXAMPLE 47-{[4-(3,4-Dichlorobenzyl)homopiperazino-(1)]propyl}-theophylline.dihydrochloride

A mixture of 3.0 g of 7-(3-bromopropyl)theophylline, 2.6 g ofN-(3,4-dichlorobenzyl)-homopiperazine and 1.4 g of anhydrous potassiumcarbonate in ethanol was refluxed under stirring for 13 hours. Thepotassium carbonate was then removed by filtration and the filtrate wasconcentrated. To the residue was added dilute hydrochloric acid, andthis was washed with chloroform and then made alkaline with diluteaqueous sodium hydroxide. An oil was separated from the aqueoussolution, and this oil was extracted with chloroform. The chloroformextract was evaporated to remove the solvent, and then the residue wasconverted to its hydrochloride in a conventional manner. Thehydrochloride thus obtained was recrystallized from methanol-ethanol togive 3.1 g of the desired7-{[4-(3,4-dichlorobenzyl)homopiperazino(1)]propyl}-theophylline.hydrochloride.M.p. 250°-255° C.

Analysis for C₂₂ H₂₈ O₂ N₆ Cl₂.2HCl.1/2H₂ O: Calculated (%): C, 47.06;H, 5.58; N, 14.97. Found (%): C, 47.36; H, 5.75; N, 14.49.

EXAMPLE 57-{[4-(3,4-Dichlorobenzoyl)homopiperazino-(1)]propyl}-theophylline.hydrochloride

A mixture of 4.8 g of 7-[3-homopiperazino-(1)]propyl-theophylline, 42 gof 10% aqueous potassium carbonate and 100 ml of chloroform was cooledwith ice, and 3.2 g of 3,4-dichlorobenzoyl chloride was added dropwiseto the mixture under cooling with ice. The chloroform phase wasseparated, washed with water and dried. The dried phase was evaporatedto remove the solvent, and the residue was converted to itshydrochloride in a conventional manner. The thus-obtained hydrochloridewas recrystallized from methanol and ethyl acetate. Thus, the desired7-{[4-(3,4-dichlorobenzoyl)homopiperazino-(1)]-propyl}-theophylline.hydrochloridewas obtained. Yield 3.0 g and m.p. 163°-167° C.

Analysis for C₂₂ H₂₆ O₃ N₆ Cl₂.HCl.2H₂ O: Calculated (%): C, 46.69; H,5.53; N, 14.85. Found (%): C, 46.88; H, 5.15; N, 15.49.

EXAMPLES 6-35

In Examples 6 through 35, the procedure described in Example 2(corresponding to the aforementioned Process A) was repeated to give thecompounds set forth in Table 2. ##STR15##

                                      TABLE 2                                     __________________________________________________________________________                                                  Analysis                        Example                                       Calculated (upper)/Found                                                      (lower)                         No.   X          R              m.p. (°C.)                                                                   Formula   C    H    N                   __________________________________________________________________________     6    (CH.sub.2).sub.2                                                                         CHO            230-235                                                                             C.sub.15 H.sub.22 O.sub.3 N.sub.6                                                       47.42                                                                              6.38 22.13                                               (dec.)                                                                              .HCl.1/2 H.sub.2 O                                                                      47.60                                                                              6.28 22.12                7    (CH.sub.2).sub.2                                                                         CH.sub.3       240-248                                                                             C.sub.15 H.sub.24 O.sub.2 N.sub.6                                                       44.77                                                                              6.78 20.89                                               (dec.)                                                                              .2HCl.1/2 H.sub.2 O                                                                     44.88                                                                              6.54 21.20                8    (CH.sub.2).sub.2                                                                                        114-115                                                                             C.sub.20 H.sub.26 O.sub.2 N.sub.6                                                       62.79 62.66                                                                        6.87 6.84                                                                          21.98 21.69          9    (CH.sub.2).sub.2                                                                          ##STR16##     100-102                                                                             C.sub.21 H.sub.26 O.sub.2 N.sub.6                                             Cl.sub.2  54.19 54.21                                                                        5.64 5.62                                                                          18.06 18.07         10    (CH.sub.2).sub.3                                                                         CH.sub.3       240-245                                                                             C.sub.16 H.sub.26 O.sub.2 N.sub.6                                                       45.17                                                                              7.12 19.76                                                     .2HCl.H.sub.2 O                                                                         45.11                                                                              7.31 19.62               11    (CH.sub.2).sub.3                                                                         CH.sub.2 CH.sub.2 CH.sub.2 OH                                                                225-227                                                                             C.sub.18 H.sub.30 O.sub.3 N.sub.6                                                       46.04                                                                              7.31 17.90                                                     .2HCl.H.sub.2 O                                                                         46.08                                                                              7.13 18.36               12    (CH.sub.2).sub.3                                                                          ##STR17##     250-256 (dec.)                                                                      C.sub.18 H.sub.30 O.sub.3 N.sub.6                                             .2HCl.1/2 H.sub.2 O                                                                     46.95 46.45                                                                        7.24 7.48                                                                          18.26 18.54         13    (CH.sub.2).sub.3                                                                          ##STR18##     195-200                                                                             C.sub.21 H.sub.28 O.sub.2 N.sub.6                                             .2HCl     53.72 53.20                                                                        6.46 6.36                                                                          17.91 17.90         14    (CH.sub.2).sub.3                                                                          ##STR19##     245-255 (dec.)                                                                      C.sub.22 H.sub.32 O.sub.2 N.sub.6                                             .2HCl     54.65 54.11                                                                        6.68 6.66                                                                          17.39  17.57        15    (CH.sub.2).sub.3                                                                          ##STR20##     250-253 (dec.)                                                                      C.sub.22 H.sub.29 O.sub.2 N.sub.6                                             Cl .2HCl.1/2 H.sub.2 O                                                                  50.14 50.18                                                                        6.13 5.99                                                                          15.95 16.31         16    (CH.sub.2).sub.3                                                                          ##STR21##     188-190                                                                             C.sub.22 H.sub.29 O.sub.2 N.sub.6                                             Cl .2HCl.2.5H.sub.2 O                                                                   46.94 46.68                                                                        6.46 5.91                                                                          14.93 15.70         17    (CH.sub.2).sub.3                                                                          ##STR22##     170-175                                                                             C.sub.22 H.sub.28 O.sub.2 N.sub.6                                             Cl.sub.2 .2HCl.H.sub.2 O                                                                46.32 46.36                                                                        5.67 5.59                                                                          14.74 14.88         18    (CH.sub.2).sub.3                                                                          ##STR23##     245-250                                                                             C.sub.22 H.sub.29 O.sub.2 N.sub.6 F                                           2HCl.H.sub.2 O                                                                          50.86 51.27                                                                        6.42 6.61                                                                          16.76 16.55         19    (CH.sub.2).sub.3                                                                          ##STR24##     250-255 (dec.)                                                                      C.sub.22 H.sub.29 O.sub.4 N.sub.7                                             .2HCl.H.sub.2 O                                                                         48.35 48.45                                                                        6.10 5.79                                                                          17.94 18.17         20    (CH.sub.2).sub.3                                                                          ##STR25##     240-245                                                                             C.sub.23 H.sub.30 O.sub.3 N.sub.6                                             .2HCl.H.sub.2 O                                                                         51.97 52.08                                                                        6.46 6.80                                                                          15.81 15.77         21    (CH.sub.2).sub.3                                                                          ##STR26##     180-185 (dec.)                                                                      C.sub.24 H.sub.34 O.sub.4 N.sub.6                                             .2HCl     51.29 50.78                                                                        6.83 7.06                                                                          14.96 14.89         22    (CH.sub.2).sub.3                                                                          ##STR27##     215-218 (dec.)                                                                      C.sub.25 H.sub.36 O.sub. 5 N.sub.6                                            .2HCl     52.35 52.04                                                                        6.69 6.88                                                                          14.66 14.89         23    (CH.sub.2).sub.3                                                                          ##STR28##     234-238                                                                             C.sub.22 H.sub.28 O.sub.2 N.sub.6                                             C.sub.2 .2HCl.1/2                                                                       47.06 46.70                                                                        5.58 5.84                                                                          14.97 14.66         24    (CH.sub.2).sub.3                                                                          ##STR29##     240-245                                                                             C.sub.19 H.sub.26 O.sub.2 N.sub.8                                             .2HCl.1/2 H.sub.2 O                                                                     47.49 47.22                                                                        6.10 6.07                                                                          23.32 22.92         25    (CH.sub.2).sub.3                                                                          ##STR30##     223-228                                                                             C.sub.23 H.sub.32 O.sub.2 N.sub.6                                             .2HCl.H.sub.2 O                                                                         53.58 53.37                                                                        7.05 7.00                                                                          16.31 16.83         26    (CH.sub.2).sub.3                                                                          ##STR31##     250-256 (dec.)                                                                      C.sub.23 H.sub.32 O.sub.2 N.sub.6                                             .2HCl.1/2 H.sub.2 O                                                                     54.53 54.26                                                                        6.98 6.92                                                                          16.60 17.14         27    (CH.sub.2).sub.4                                                                          ##STR32##     264-268 (dec.)                                                                      C.sub.23 H.sub.31 O.sub.2 N.sub.6                                             Cl .2HCl.1/2 H.sub.2 O                                                                  51.06 51.25                                                                        6.35 6.30                                                                          15.54 15.41         28    (CH.sub.2).sub.4                                                                          ##STR33##     250-255 (dec.)                                                                      C.sub.23 H.sub.31 O.sub.2 N.sub.6 F                                           2HCl.1/2 H.sub.2 O                                                                      52.66 52.37                                                                        6.55 6.39                                                                          16.03 16.29         29    (CH.sub.2).sub.4                                                                          ##STR34##     259-262 (dec.)                                                                      C.sub.23 H.sub.31 O.sub.4 N.sub.7                                             .2HCl.1/2 H.sub.2 O                                                                     50.08 49.85                                                                        6.23 6.13                                                                          17.78 17.79         30    (CH.sub.2).sub.3                                                                         COCH.sub.2 CH.sub.2 CH.sub.3                                                                 140-145                                                                             C.sub.19 H.sub.30                                                                       51.27.3 N.sub.6                                                                    7.49 18.89                                                     .HCl.H.sub.2 O                                                                          51.55                                                                              7.56 19.33               31    (CH.sub.2).sub.3                                                                          ##STR35##     190-195                                                                             C.sub.23 H.sub.30 O.sub.5 N.sub.6 S                                           HCl.H.sub.2 O                                                                           49.59 49.42                                                                        5.80 5.79                                                                          15.09 14.78         32    (CH.sub.2).sub.3                                                                          ##STR36##     251-255                                                                             C.sub.24 H.sub.30 O.sub.3 N.sub.6                                             .HCl.H.sub.2 O                                                                          57.07 56.99                                                                        6.60 6.58                                                                          16.64 16.91         33                                                                                   ##STR37## CH.sub.3       260-266                                                                             C.sub.16 H.sub.26 O.sub.3 N.sub.6                                             .HCl.1/2 H.sub.2 O                                                                      44.44 44.43                                                                        6.77 6.55                                                                          19.44 19.50         34    (CH.sub.2).sub.6                                                                          ##STR38##     231-233                                                                             C.sub.25 H.sub.35 O.sub.2 N.sub.6                                             Cl .2HCl  53.61 53.13                                                                        6.67 6.52                                                                          15.01  15.27        35    (CH.sub.2).sub.6                                                                          ##STR39##     185-187                                                                             C.sub.25 H.sub.34 O.sub.2 N.sub.6                                             Cl.sub.2 .2HCl                                                                          50.51 49.10                                                                        6.12 5.95                                                                          14.14 13.91         __________________________________________________________________________

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
 1. A compound having the formula: ##STR40## wherein X is --(CH₂)_(n) --, in which n is an integer of 1 to 6, or ##STR41## and R is: (1) a group having the formula ##STR42## wherein Y₁, Y₂ and Y₃, which can be the same or different, each is hydrogen, lower alkyl, lower alkoxy, lower alkylsulfonyl, halogen or nitro; or(2) ##STR43## and pharmacologically acceptable acid addition salts thereof.
 2. A compound having the formula: ##STR44## in which n is an integer of 1 to 6; A is --(CH₂)_(m) --, in which m is an integer of 0 to 2; and Y₁, Y₂ and Y₃, which can be the same or different, are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, lower alkylsulfonyl, halogen or nitro, with the proviso that at least one of Y₁, Y₂ and Y₃ is halogen or nitro, and pharmacologically acceptable acid addition salts thereof.
 3. A compound as claimed in claim 2, wherein n is
 3. 4. A compound according to claim 2 having the formula: ##STR45##
 5. A compound according to claim 2 having the formula: ##STR46##
 6. A compound having the formula: ##STR47## wherein n is an integer of from 1 to 6, and each of Y₁, Y₂ and Y₃, which can be the same or different, represent hydrogen or chlorine, with the proviso that at least one of Y₁, Y₂ and Y₃ is chlorine.
 7. A compound according to claim 6, wherein n is
 3. 8. A compound according to claim 7 having the formula: ##STR48##
 9. A compound according to claim 7 having the formula: ##STR49##
 10. A compound according to claim 7 having the formula: ##STR50##
 11. A compound according to claim 7 having the formula: ##STR51## 